Haloperidol and clozapine have dissociable effects in a model of attentional performance deficits induced by blockade of NMDA receptors in the mPFC

Abstract

Cognitive impairment in schizophrenia is particularly evident in the domains of attention and executive functions. Atypical antipsychotics are somewhat more effective than conventional antipsychotics in improving cognitive functioning in these patients. The aim of this study was to compare the effects of conventional and atypical antipsychotics in a model of attentional performance deficit of schizophrenia induced by blockade of N-methyl-D: -aspartate (NMDA) receptors in the medial prefrontal cortex. Attentional performance was assessed using the five-choice serial reaction time task. The task provides indices of attentional functioning (% correct responses), executive control (measured by anticipatory and perseverative responding), decision time (measured by correct response latency), and omissions. Haloperidol and clozapine were given intraperitoneally (IP) to animals that had received vehicle or a competitive NMDA receptor antagonist, 3-(R)-2-carboxypiperazin-4-propyl-1-phosphonic acid (CPP), directly into the medial prefrontal cortex. Fifty nanograms/side of CPP reduced accuracy (% correct responses) and increased anticipatory and perseverative responding. Haloperidol (0.03 mg/kg IP) reduced the CPP-induced anticipatory and perseverative overresponding but not the impairment in accuracy. In contrast, clozapine (2.5 mg/kg IP) reversed the decrease in accuracy and impulsivity (anticipatory responding) but not perseverative overresponding. CPP increased decision time and omissions, but these effects were not affected by either haloperidol or clozapine. The effects on "impulsivity" and "compulsive perseveration" in a rat model of attentional and executive deficit of schizophrenia might differentiate conventional and atypical antipsychotics. Antagonistic activity at 5-HT(2A) receptors may best explain the facilitatory effects of clozapine on cognition.